{"doi":"10.1101/2025.07.21.665979","title":"A Supramolecular Self-assembly Approach to Site-Specific Antibody Conjugates <i>via</i> a Coiled-coil Peptides Platform","abstract":"Antibody conjugates play a central role across multiple healthcare sectors with a prime example being antibody-drug conjugates (ADCs). Although widely used lysine and hinge cysteine conjugation methods yield products, the lack of site-specificity and spatial control along with the highly heterogeneous composition are significant limitations. We describe a facile supramolecular assembly method based on heterodimer coiled-coil formation for site-specific antibody conjugation. The method affords uniform loading of diverse payloads including anti-cancer agents, polymers, enzymes, fluorophores, etc. under mild aqueous conditions. Further, the facile convergent approach capitalizes on the independent strengths and flexibility of protein expression and peptide chemistry culminating in a final self-assembly step. Coiled-coil conjugation perseveres both antibody antigen binding sites for target engagement and heavy chains constant domains for Fc binding and recycling. An ADC loaded with monomethyl auristatin E targeting HER2+ tumors significantly reduces tumor volume in a human ovarian cancer xenograft model outperforming the antibody alone with validated performance against a best-in-class therapeutic. Supramolecular assembly-driven bioconjugation expands the bioorthogonal chemistry toolbox for antibody modification and opens new avenues for advanced antibody conjugates with multiple payloads.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":571991,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":269957,"name":"Ting‐Yu Shih","orcid":"0000-0003-1733-0447","position":1,"is_corresponding":false},{"id":290956,"name":"Mark W. Grinstaff","orcid":"0000-0002-5453-3668","position":2,"is_corresponding":false},{"id":1477944,"name":"A. Ringaci","orcid":"0000-0001-6951-4032","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":null,"created_at":"2026-07-19T02:57:19.669553Z","pmid":"40777265","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}